Process for preparing 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds

Abstract

6-(Substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compounds possessing strong platelet aggregation inhibiting activity and blood pressure depressing activity, having the general formula: ##STR1## wherein R 1 is hydrogen or lower alkyl; R 2 is hydrogen, lower alkyl, lower alkylthio or the grouping R 5 --NH-- where R 5 is lower alkyl; R 3 is phenyl, pyridyl, benzyl, lower alkyl or a substituted phenyl group carrying at any desired position on the benzene ring thereof the grouping: ##STR2## where R 1 has the same meaning as given above; R 4 is hydrogen or halogen; n is 0 or 1; and when both R 2 and R 3 are lower alkyl groups, R 2 and R 3 may be combined together with the bridging member ##STR3## between them to form the structure: ##STR4## where m is 2 or 3, as well as physiologically acceptable acid-addition salts thereof, and processes for preparing them.

What is claimed is: 
     
       1. A process for the preparation of a 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compound of the formula: ##STR19## wherein R 1  is a hydrogen atom or a lower alkyl group; R 2  is a hydrogen atom, a lower alkyl group, a lower alkylthio group or the grouping R 5  -NH--where R 5  is a lower alkyl group; R 3  is a phenyl group, a pyridyl group, a benzyl group, a lower alkyl group or a substituted phenyl group carrying at the para-position (4-position) on the benzene ring thereof the grouping: ##STR20## wherein R 1  has the same meaning as given above; R 4  is a hydrogen atom or a halogen atom; n is 0 or 1; and when both R 2  and R 3  are lower alkyl groups, R 2   an R 3  may be combined together with the bridging member ##STR21## between them to form the structure: ##STR22## wherein m is 2 or 3, or a physiologically acceptable acid-addition salt thereof, which comprises reacting a 6-(3-R 4  -4-amino- or 3-R 4  -4-aminoalkyl-phenyl)-4,5-dihydro-3(2H)-pyridazinone with a thioisocyanate of the formula R 3  '-NCS where R 3  ' is a phenyl, pyridyl or benzyl group or a lower alkyl group to form a thiourea derivative of the formula: ##STR23## wherein R 1 , R 3  ', R 4  and n have the same meanings as given above, reacting the thiourea derivative with a methyl halide to prepare the corresponding methylisothiuronium salt of the formula: ##STR24## wherein X is a halogen atom and R 1 , R 3  ', R 4  and n have the same meanings as given above, and then reacting the methylisothiuronium salt with an amine or diamine of the formula: ##STR25## wherein R is a pyridyl, benzyl or phenyl group or a lower alkyl group and m is 2 or 3. 
     
     
       2. A process according to claim 1, further comprising the step of converting the compound resulting from the reaction with the amine or diamine into a physiologically acceptable acid-addition salt. 
     
     
       3. A process for the preparation of a 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compound of the formula: ##STR26## wherein R 1  is a hydrogen atom or a lower alkyl group; R 2  ' is a hydrogen atom or a lower alkyl group; R 3  ' is a phenyl or pyridyl group; and R 4  is a hydrogen atom or a halogen atom, or a physiologically acceptable acid-addition salt thereof, which comprises reacting an imidate or an imidoyl halide of the formula: ##STR27## where R 2  ' and R 3  ' have the same meanings as given above and X is a halogen atom, with a pyridazinone derivative of the formula: ##STR28## wherein R 1 , R 4  and n have the same meanings as given above. 
     
     
       4. A process according to claim 3, further comprisng the step of converting the resulting compound into a physiologically acceptable salt thereof. 
     
     
       5. A process for the preparation of a 6-(substituted phenyl)-4,5-dihydro-3(2H)-pyridazinone compound of the formula: ##STR29## wherein R 1  is a hydrogen atom or a lower alkyl group, R 4  is a hydrogen atom or a halogen atom and n is 0 or 1, or a physiologically acceptable acid-addition salt thereof, which comprises reacting a pyridazinone derivative of the formula: ##STR30## wherein R 1 , R 4  and n have the same meanings as given above, with a compound of the formula: ##STR31## wherein R 5  is a lower alkyl group and R 1  has the same meaning as given above. 
     
     
       6. A process according to claim 5, further comprising the step of converting the resulting compound into a physiologically acceptable salt thereof. 
     
     
       7. A process according to claim 1, wherein said methyl halide is methyl iodide. 
     
     
       8. A process according to claim 1, wherein said amine or diamine is a member selected from the group consisting of methylamine, ethylamine, propylamine, isopropylamine, butylamine, aniline, benzylamine, 2-, 3- and 4-aminopyridines, ethylenediamine and trimethylenediamine. 
     
     
       9. A process according to claim 2, wherein said compound of the formula (I) is converted into a physiologically acceptable acid-addition salt thereof by reaction with a member selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, succinic acid, tartaric acid and citric acid. 
     
     
       10. A process according to claim 4, wherein said compound of the formula (I) is converted into a physiologically acceptable acid-addition salt thereof by reaction with a member selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, succinic acid, tartaric acid and citric acid. 
     
     
       11. A process according to claim 5, wherein said compound of the formula (V) is ethylorthoformate or ethylorthoacetate. 
     
     
       12. A process according to claim 6, wherein said compound of the formula (I) is converted into a physiologically acceptable acid-addition salt thereof by reaction with a member selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, succinic acid, tartaric acid and citric acid.